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Ch. 12 Body Defenses (Image by Volker Brinkman and Abdul Hakkim).

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1 Ch. 12 Body Defenses (Image by Volker Brinkman and Abdul Hakkim).

2 Outline Immune system Non-specific response Specific response

3 Defenses Against Pathogens pathogens – environmental agents capable of producing disease – infectious organisms, toxic chemicals, and radiation three lines of defense against pathogens: – first line of defense – external barriers, skin and mucous membranes – second line of defense – several nonspecific defense mechanisms leukocytes and macrophages, antimicrobial proteins, immune surveillance, inflammation, and fever effective against a broad range of pathogens – third line of defense – the immune system defeats a pathogen, and leaves the body with a ‘memory’ of it so it can defeat it faster in the future

4 External Barriers skin – makes it mechanically difficult for microorganisms to enter the body – too dry and nutrient-poor to support microbial growth – defensins – peptides that kill microbes by creating holes in their membranes – acid mantle – thin film of lactic acid from sweat inhibits bacterial growth mucous membranes – digestive, respiratory, urinary, and reproductive tracts are open to the exterior and protected by mucous membranes – mucus physically traps microbes – lysozyme - enzyme destroys bacterial cell walls subepithelial areolar tissue – viscous barrier of hyaluronic acid hyaluronidase - enzyme used by pathogens to make hyaluronic acid less viscous

5 Leukocytes and Macrophages phagocytes – phagocytic cells with a voracious appetite for foreign matter five types of leukocytes – neutrophils – eosinophils – basophils – monocytes – lymphocytes

6 Neutrophils wander in connective tissue killing bacteria – phagocytosis and digestion – produces a cloud of bactericidal chemicals – NETs create a killing zone – degranulation lysosomes discharge into tissue fluid – respiratory burst – neutrophils rapidly absorb oxygen toxic chemicals are created (O 2. -, H 2 O 2, HClO) – kill more bacteria with toxic chemicals than phagocytosis

7 Eosinophils Found mucous membranes Defend mainly against parasites, allergens kill tapeworms and roundworms by producing superoxide, hydrogen peroxide, and toxic proteins promote action of basophils and mast cells phagocytize antigen-antibody complexes limit action of histamine and other inflammatory chemicals

8 Basophils secrete chemicals that aid mobility and action of WBC other leukocytes – leukotrienes – activate and attract neutrophils and eosinophils – histamine – a vasodilator which increases blood flow speeds delivery of leukocytes to the area – heparin – inhibits the formation of clots would impede leukocyte mobility mast cells also secrete these substances – type of connective tissue cell very similar to basophils

9 Monocytes monocytes - emigrate from blood into the connective tissue and transform into macrophages macrophage system – all the body’s avidly phagocytic cells, except leukocytes – wandering macrophages – actively seeking pathogens widely distributed in loose connective tissue – fixed macrophages – phagocytize only pathogens that come to them microglia – in central nervous system alveolar macrophages – in lungs hepatic macrophages – in liver

10 Antimicrobial Proteins proteins that inhibit microbial reproduction and provide short-term, nonspecific resistance to pathogenic bacteria and viruses two families of antimicrobial proteins: – interferons – complement system

11 Complement System complement system – a group of 30 or more globular proteins that make powerful contributions to both nonspecific resistance and specific immunity – activated complement brings about four methods of pathogen destruction inflammation immune clearance phagocytosis cytolysis – three routes of complement activation classical pathway alternative pathway lectin pathway

12 Complement System classical pathway – requires antibody molecule to get started – thus part of specific immunity – antibody binds to antigen on surface of the pathogenic organism forms antigen-antibody (Ag-Ab) complex – changes the antibody’s shape exposing a pair of complement-binding sites binding of complement (C1) sets off a reaction cascade called complement fixation – results in a chain of complement proteins attaching to the antibody alternative pathway – nonspecific, do not require antibody – C3 breaks down in the blood to C3a and C3b C3b binds directly to targets such as human tumor cells, viruses, bacteria, and yeasts triggers cascade reaction with autocatalytic effect where more C3 is formed lectin pathway – lectins – plasma proteins that bind to carbohydrates bind to certain sugars of a microbial cell surface sets off another cascade of C3 production

13 21-13 Complement Activation Figure 21.15 C3a C3b Four mechanisms of pathogen destruction Inflammation Cytolysis Opsonization Phagocytosis Reaction cascade Classical pathway (antibody-dependent) Antigen–antibody complexes form on pathogen surface Reaction cascade (complement fixation) Alternative pathway (antibody-independent) C3 dissociates into fragments C3a and C3b C3b binds to pathogen surface Reaction cascade and autocatalytic effect C3 dissociates into C3a and C3b Lectin pathway (antibody-independent) Lectin binds to carbohydrates on pathogen surface Splits C5 into C5a and C5b Coats bacteria, viruses, and other pathogens Binds Ag–Ab complexes to RBCs Stimulates neutrophil and macrophage activity Binds to basophils and mast cells Release of histamine and other inflammatory chemicals RBCs transport Ag–Ab complexes to liver and spleen C5b binds C6, C7, and C8 C5b678 complex binds ring of C9 molecules Phagocytes remove and degrade Ag–Ab complexes Membrane attack complex Immune clearance Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

14 21-14 Membrane Attack Complex complement proteins form ring in plasma membrane of target cell causing cytolysis Figure 21.16 C5b C6 C7 C8 C9 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

15 Immune Surveillance immune surveillance – a phenomenon in which natural (NK) killer cells continually patrol the body on the lookout for pathogens and diseased host cells. natural killer (NK) cells attack and destroy: – bacteria, cells of transplanted organs, cells infected with viruses, and cancer cells recognizes enemy cell and binds release proteins called perforins – polymerize a ring and create a hole in its plasma membrane secrete a group of protein degrading enzymes – granzymes – degrade cellular enzymes and induce apoptosis Macrophage

16 Inflammation inflammation – local defensive response to tissue injury of any kind, including trauma and infection general purposes of inflammation – limit spread of pathogens, then destroys them – remove debris from damaged tissue – initiate tissue repair four cardinal signs of inflammation - redness - swelling - heat - pain

17 Inflammation suffix -itis denotes inflammation of specific organs: arthritis, pancreatitis, dermatitis cytokines – class of chemicals that regulate inflammation and immunity – secreted mainly by leukocytes – alter the physiology or behavior of receiving cell – act at short range, neighboring cells (paracrines) or the same cell that secretes them (autocrines) – include interferon, interleukins, tumor necrosis factor, chemotactic factors, and others

18 Processes of Inflammation three major processes of inflammation – mobilization of body defenses Hyperemia Vasodilation – containment and destruction of pathogens Fibrinogen Heparin Neutrophils attracted by chemotaxis – tissue cleanup and repair Monocytes arrive in 8-12 hours Edema Platelet-derived growth factor

19 Mobilization of Defenses leukocyte behavior – margination selectins cause leukocytes to adhere to blood vessel walls – diapedesis (emigration) leukocytes squeeze between endothelial cells into tissue space Figure 21.19 Splinter Phagocytosis 1 5 Chemotaxis 4 2 Mast cells Margination Diapedesis 3 Neutrophils Bacteria From damaged tissue Inflammatory chemicals From mast cells From blood Increased permeability Blood capillary or venule Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

20 Specific Immunity immune system – composed of a large population of widely distributed cells that recognize foreign substances and act to neutralize or destroy them two characteristics distinguish immunity from nonspecific resistance – specificity – immunity directed against a particular pathogen – memory – when re-exposed to the same pathogen, the body reacts so quickly that there is no noticeable illness two types of immunity – cellular (cell-mediated) immunity: (T cells) lymphocytes directly attack and destroy foreign cells or diseased host cells rids the body of pathogens that reside inside human cells, where they are inaccessible to antibodies kills cells that harbor them – humoral (antibody-mediated) immunity: (B cells) mediated by antibodies that do not directly destroy a pathogen indirect attack where antibodies assault the pathogen can only work against the extracellular stage of infectious microorganisms

21 Passive and Active Immunity natural active immunity – production of one’s own antibodies or T cells as a result of infection or natural exposure to antigen artificial active immunity – production of one’s own antibodies or T cells as a result of vaccination against disease natural passive immunity – temporary immunity that results from antibodies produced by another person fetus acquires antibodies from mother through placenta, milk artificial passive immunity – temporary immunity that results from the injection of immune serum (antibodies) from another person or animal treatment for snakebite, botulism, rabies, tetanus, and other diseases

22 Antigens Antigen – any molecule that triggers an immune response – Large molecular weights of over 10,000 amu – Proteins, polysaccharides, glycoproteins, glycolipids Epitopes (antigenic determinants) – certain regions of an antigen molecule that stimulate immune responses Haptens - to small to be antigenic in themselves – must combine with a host macromolecule – create a unique complex that the body recognizes as foreign – cosmetics, detergents, industrial chemicals, poison ivy, and animal dander

23 Lymphocytes major cells of the immune system – lymphocytes – macrophages – dendritic cells especially concentrated in strategic places such as lymphatic organs, skin, and mucous membranes three categories of lymphocytes – natural killer (NK) cells – immune surveillance – T lymphocytes (T cells) – B lymphocytes (B cells)

24 Life Cycle of T cells ‘Born’ in the red bone marrow – descendant of PPSCs, released into blood, colonize thymus Mature in thymus – thymosins stimulate maturing T cells to develop surface antigen receptors – with receptors in place, the T cells are now immunocompetent – capable of recognizing antigens presented to them by APCs – Tested by reticuloendothelial cells, present ‘self’ antigens to them – two ways to fail the test: inability to recognize the RE cells, especially their MHC antigens – would be incapable of recognizing a foreign attack on the body reacting to the self antigen – T cells would attack one’s own tissues Negative selection – Clonal deletion – Anergy Self tolerance and positive selection – Naïve T-cells Deployment – Leave thymus, colonize lymphatic tissues and organs

25 B Lymphocytes (B cells) site of development – group fetal stem cells remain in bone marrow – develop into B cells B cell selection – B cells that react to self antigens undergo either anergy or clonal deletion same as T cell selection self-tolerant B cells synthesize antigen surface receptors, divide rapidly, produce immunocompetent clones leave bone marrow and colonize same lymphatic tissues and organs as T cells

26 Antigen-Presenting Cells (APCs) T cells can not recognize antigens on their own Antigen-presenting cells (APCs) are required to help – dendritic cells, macrophages, reticular cells, and B cells function as APCs Function of APCs depends on major histocompatibility complex (MHC) proteins – act as cell ‘identification tags’ that label every cell of your body as belonging to you – structurally unique for each individual, except for identical twins Antigen processing – APC encounters antigen – internalizes it by endocytosis and digests – displays epitopes in grooves of the MHC protein Antigen presenting – Wander T cell detects an APC with a nonself-antigen, immune attack initiated – Communicate via interleukins

27 Antigen Processing Figure 21.21a Phagosome Epitopes MHC protein (a) 2 3 4 5 6 1 Phagocytosis of antigen Lysosome fuses with phagosome Antigen and enzyme mix in phagolysosome Antigen is degraded Antigen residue is voided by exocytosis Processed antigen fragments (epitopes) displayed on macrophage surface Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

28 Cellular Immunity cellular (cell-mediated) immunity – a form of specific defense in which the T lymphocytes directly attack and destroy diseased or foreign cells, and the immune system remembers the antigens and prevents them from causing disease in the future both cellular and humoral immunity occur in three stages: – recognition – attack – memory

29 Cellular Immunity cellular immunity involves four classes of T cells – cytotoxic T (T C ) cells – killer T cells (T8, CD8, or CD8+) the ‘effectors’ of cellular immunity carry out attack on enemy cells – helper T (T H ) cells (T4, CD4, CD4+) help promote T C cell and B cell action and nonspecific resistance – regulatory T (T R ) cells – T-regs inhibit multiplication and cytokine secretion by other T cells limit immune response – memory (T M ) cells descend from the cytotoxic T cells responsible for memory in cellular immunity

30 T Cell Recognition recognition phase has two aspects: antigen presentation and T cell activation antigen presentation – APC encounters and processes an antigen – migrates to nearest lymph node – displays it to the T cells – when T cell encounters its displayed antigen on the MHC protein, they initiate the immune response – T cells respond to two classes of MHC proteins MHC – I proteins – occur on every nucleated cells in the body – constantly produced by our cells, transported to, and inserted on plasma membrane – normal self antigens that do not elicit and T cell response – viral proteins or abnormal cancer antigens do elicit a T cell response – infected or malignant cells are then destroyed before they can do further harm to the body MHC – II proteins (human leukocyte antigens – HLAs) – occur only on APCs and display only foreign antigens – T C cells respond only to MHC – I proteins – T H cells respond only to MHC – II proteins

31 T cell Activation Figure 21.22 Costimulation Clonal selection MHC protein Antigen APC T C or T H TCTC TCTC TCTC TCTC THTH THTH TMTM TMTM TMTM THTH THTH or Effector cells APC 4 Activity of NK, B, or T C cells Development of memory T cells Inflammation and other nonspecific defenses or 1 2 3 Lethal hit4 Costimulation protein T C or T H Memory T cells MHC-II protein Interleukin secretion Destruction of enemy cell Enemy cell MHC-I protein Antigen recognition Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

32 21-32 Attack : Role of Helper T (T H ) Cells Figure 21.23 Macrophage, B cell, or other antigen-presenting cell Macrophage- activating factor Other cytokines Macrophage activity Leukocyte chemotaxis Inflammation Interleukin-1 Other cytokines Interleukin-2 Other cytokines Clonal selection of cytotoxic T cells Clonal selection of B cells Humoral immunityCellular immunityNonspecific defense Helper T (T 4 ) cell Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

33 Attack : Cytotoxic T (T C ) Cells cytotoxic T (T C ) cell are the only T cells directly attack other cells when T C cell recognizes a complex of antigen and MHC – I protein on a diseased or foreign cell it ‘docks’ on that cell – delivers a lethal hit of toxic chemicals perforin and granzymes – kill cells in the same manner as NK cells interferons – inhibit viral replication – recruit and activate macrophages tumor necrosis factor (TNF) – aids in macrophage activation and kills cancer cells – goes off in search of another enemy cell while the chemicals do their work

34 21-34 Cytotoxic T Cell Function cytotoxic T cell binding to cancer cell Figure 21.24 a-b (a)(b) Cancer cell T cell Dying cancer cell 10 µm Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Dr. Andrejs Liepins

35 Memory immune memory follows primary response following clonal selection, some T C and T H cells become memory cells – long-lived – more numerous than naïve T cells – fewer steps to be activated, so they respond more rapidly T cell recall response – upon re-exposure to same pathogen later in life, memory cells launch a quick attack so that no noticeable illness occurs – the person is immune to the disease

36 Humoral Immunity humoral immunity is a more indirect method of defense than cellular immunity B lymphocytes of humoral immunity produce antibodies that bind to antigens and tag them for destruction by other means – cellular immunity attacks the enemy cells directly works in three stages like cellular immunity – recognition – attack – memory

37 Humoral Immunity recognition – immunocompetent B cell has thousands of surface receptors for one antigen – activation begins when an antigen binds to several of these receptors – usually B cell response goes no further unless a helper T cell binds to this Ag-MHCP complex bound T H cell secretes interleukins that activate B cell – triggers clonal selection B cell mitosis gives rise to an entire battalion of identical B cells programmed against the same antigen most differentiate into plasma cells larger than B cells and contain an abundance of rough ER secrete antibodies at a rate of 2,000 molecules per second during their life span of 4 to 5 days antibodies travel through the body in the blood or other body fluids – first exposure antibodies IgM, later exposures to the same antigen, IgG attack – antibodies bind to antigen, render it harmless, ‘tag it’ for destruction memory – some B cells differentiate into memory cells

38 Humoral Immunity - Recognition Figure 21.25 Plasma cells Antibody Antigen Receptor Helper T cell Epitope MHC-II protein Interleukin B cell 1 2 3 4 5 Antigen recognition Immunocompetent B cells exposed to antigen. Antigen binds only to B cells with complementary receptors. Antigen presentation B cell internalizes antigen and displays processed epitope. Helper T cell binds to B cell and secretes interleukin. Clonal selection Interleukin stimulates B cell to divide repeatedly and form a clone. Differentiation Some cells of the clone become memory B cells. Most differentiate into plasma cells. Attack Plasma cells synthesize and secrete antibody. Antibody employs various means to render antigen harmless. Lymphocyte Memory B cell Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

39 B cells and Plasma cells Figure 21.26 a-b Mitochondria Nucleus (a) B cell (b) Plasma cell2 µm Rough endoplasmic reticulum 2 µm Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. © Dr. Don W. Fawcett/Visuals Unlimited

40 Antibodies immunoglobulin (Ig) – an antibody is a defensive gamma globulin found in the blood plasma, tissue fluids, body secretions, and some leukocyte membranes antibody monomer – the basic structural unit of an antibody

41 Five Classes of Antibodies named for the structure of their C region – IgA - monomer in plasma; dimer in mucus, saliva, tears, milk, and intestinal secretions prevents pathogen adherence to epithelia and penetrating underlying tissues provides passive immunity to newborns – IgD - monomer; B cell transmembrane antigen receptor thought to function in B cell activation by antigens – IgE - monomer; transmembrane protein on basophils and mast cells stimulates release of histamine and other chemical mediators of inflammation and allergy – attracts eosinophils to parasitic infections – produces immediate hypersensitivity reactions – IgG - monomer; constitutes 80% of circulating antibodies crosses placenta to fetus, secreted in secondary immune response, complement fixation – IgM – pentamer in plasma and lymph secreted in primary immune response, agglutination, complement fixation

42 Humoral Immunity - Attack neutralization – antibodies mask pathogenic region of antigen complement fixation – antigen binds to IgM or IgG, antibody changes shape, initiates complement binding which leads to inflammation, phagocytosis, immune clearance, or cytolysis – primary defense against foreign cells, bacteria, and mismatched RBCs agglutination – antibody has 2-10 binding sites; binds to multiple enemy cells immobilizing them from spreading precipitation – antibody binds antigen molecules (not cells); creates antigen-antibody complex that precipitates, phagocytized by eosinophils

43 Agglutination and Precipitation Figure 21.28 a-b Antigens (a) (b) Antibodies (IgM) Antibody monomers Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

44 Humoral Immunity - Memory primary immune response – immune reaction brought about by the first exposure to an antigen – appearance of protective antibodies delayed for 3 to 6 days while naïve B cells multiply and differentiate into plasma cells – as plasma cells produce antibodies, the antibody titer (level in the blood plasma) rises IgM appears first, peaks in about 10 days, soon declines IgG levels rise as IgM declines, but IgG titer drops to a low level within a month – primary response leaves one with an immune memory of the antigen during clonal selection, some of the clone becomes memory B cells found mainly in germinal centers of the lymph nodes mount a very quick secondary (anamnestic) response

45 Humoral Immunity Responses Figure 21.29 Serum antibody titer Primary response IgM IgG Secondary response 00 5 510 15 20 25 Days from first exposure to antigen Days from reexposure to same antigen Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

46 Immunodeficiency Diseases immune system fails to react vigorously enough Severe Combined Immunodeficiency Disease (SCID) – hereditary lack of T and B cells – vulnerability to opportunistic infection and must live in protective enclosures Figure 21.30 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. © Science VU/Visuals Unlimited

47 Acquired Immunodeficiency Syndrome (AIDS) – nonhereditary diseases contracted after birth group of conditions that involve and severely depress the immune response caused by infection with the human immunodeficiency virus (HIV) – HIV structure (next slide) – invades helper T cells, macrophages and dendritic cells by “tricking” them to internalize viruses by receptor mediated endocytosis – reverse transcriptase (retrovirus) uses viral RNA as template to synthesize DNA new DNA inserted into host cell DNA (may be dormant for months to years) when activated, it induces the host cell to produce new viral RNA, capsid proteins, and matrix proteins they are coated with bits of the host cell’s plasma membrane adhere to new host cells and repeat the process Immunodeficiency Diseases

48 HIV Structure Figure 21.31a Envelope: Glycoprotein Phospholipid Matrix Capsid RNA (a) Reverse transcriptase Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

49 AIDS by destroying T H cells, HIV strikes at the central coordinating agent of nonspecific defense, humoral immunity, and cellular immunity incubation period ranges from several months to 12 years signs and symptoms – early symptoms: flulike symptoms of chills and fever – progresses to night sweats, fatigue, headache, extreme weight loss, lymphadenitis – normal T H count is 600 to 1,200 cells/  L of blood, but in AIDS it is less than 200 cells/  L – person susceptible to opportunistic infections (Toxoplasma, Pneumocystis, herpes simplex virus, cytomegalovirus, or tuberculosis) – Candida (thrush): white patches on mucous membranes – Kaposi sarcoma: cancer originates in endothelial cells of blood vessels causes purple lesions in skin

50 HIV Transmission through blood, semen, vaginal secretions, breast milk, or across the placenta most common means of transmission – sexual intercourse (vaginal, anal, oral) – contaminated blood products – contaminated needles not transmitted by casual contact undamaged latex condom is an effective barrier to HIV, especially with spermicide nonoxynol-9

51 Treatment Strategies prevent binding to CD4 proteins of T H cells disrupt reverse transcriptase to inhibit assembly of new viruses or their release from host cells medications – none can eliminate HIV, all have serious side-effects – HIV develops drug resistance medicines used in combination – AZT (azidothymidine) first anti-HIV drug - inhibits reverse transcriptase – protease inhibitors inhibit enzymes HIV needs to replicate – now more than 24 anti-HIV drugs on the market

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